GPR: 2020 - Week 47

• GPR Quiz
• Answer
• DDx1
• DDx2
• DDx3
• Acknowledgments
• Reference(s)

Clinical history

62 year old male, former beach lifeguard for 25 years, presents with new large growth on his back.

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TERT Promoter mutations A 2017 Nature paper that conducted whole genome sequencing on 183 melanoma samples found 86% of cutaneous melanomas were mutated at 1 of 4 TERT promoter sites. All 4 create new binding sites for ETS family TF GABP Generally mutually exclusive Only found in 11% of acral and mucosal melanomas

BRAF mutation BRAF mutations are present in approximately 50% of cutaneous melanoma tumors Most commonly V600E V600K is next most common variant K601 mutations are also recurrent

RAS family mutation 30-35% of melanomas contain mutations in RAS family member genes NRAS mutations are most common at 28%. These occur at recurrent hotspots HRAS and KRAS mutations are less frequent and may or may not be drivers NRAS mutations, but not HRAS/KRAS, are generally mutually exclusive with BRAF mutations

NF1 gene mutation NF1 gene mutations occur in 14-17% of melanoma cases Mutations occur throughout gene body Can be point, INDELs, structural variants Activate MAPK pathway through loss of function (BRAF, RAS mutations are activating mutations that activate MAPK pathway).

• Dr. Jochen Lennerz for conceptual inspiration
• Dr. T. Leif Helland for gross image

• Hayward, N., Wilmott, J., Waddell, N. et al. Whole-genome landscapes of major melanoma subtypes. Nature 545, 175–180 (2017). https://doi.org/10.1038/nature22071

• The Cancer Genome Atlas Network. Genomic Classification of Cutaneous Melanoma. Cell 161(7): 1681–1696 (2015). https://dx.doi.org/10.1016%2Fj.cell.2015.05.044

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This week's Gross Pathology Roundup was presented by Tyler Miller MD, PhD on 2020-11-16.